Hypercholesterolemia is known to be one of the prime etiological components of cardiovascular disease such as atherosclerosis, and there is still no effective antihypercholesterolemic agent available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compaction and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof. One group of totally synthetic analogs are disclosed in U.S. Pat. No. 4,375,475 and have the general structural formula: ##STR2## wherein R is ##STR3## In the usual course of synthesis of these lactones an intermediate ester and dihydroxy acid are encountered: ##STR4## Each of these entities, as well as the lactone, demonstrate antihypercholesterolemic activity in vivo, of comparable magnitude. However, for these compounds to manifest a useful degree of activity, it is essential that the compounds have the particular 3R:5S/3S:5R steric relationship shown in the structures.
The synthesis of these compounds comprises reduction of substrates 1a or 1b ##STR5## but the prior art methodology exhibited no stereoselectivity producing mixtures of the 3R,5R/3S,5S; and 3S,5R/3R,5S racemates in approximately 1:1 ratios. The enormously expensive procedures required to separate these diastereomers and the need to discard the unwanted half of the product made these products commercially unattractive.
Reduction of substrates of this type have been reported with sodium borohydride in U.S. Pat. No. 4,255,444; and with zinc borohydride by Hsu et al in J. Amer. Chem. Sec., 105, 593-601 (1983); and by Narasaka et al in Chemistry Letters, 1415-1418 (1980) who disclosed the use of tri-n-butylborane and sodium borohydride at low temperature. The latter system provided considerable stereoselectivity, but in the examples given none of the substrates included other functional groups which could conceivably participate in the reductive process.
Now, with the present invention it is shown that the process unexpectedly is indeed applicable to compounds with a third functional group and that it is highly efficient with yields of 90% or greater and highly stereoselective, the product being better than 90% the desired diastereomer, (whereas the prior art procedures gave no better than about 60% stereoselectivity) thereby eliminating the necessity for industrially very unattractive chromatographic or other procedures for separation of isomers and making the antihypercholesterolemic agents discussed above readily available on a commercial scale.